The study of pharmacokinetics describes the absorption, distribution, and elimination of the active drug and metabolites in quantitative terms (see Chapter 1). Ideally, a pharmacokinetic model uses the observed time course for drug concentration in the body and, from this data, obtains various pharmacokinetic parameters to predict drug dosing outcomes, pharmacodynamics, and toxicity.
In developing a model, certain underlying assumptions are made by the pharmacokineticist as to the type of pharmacokinetic model, the order of the rate process, the blood flow to a tissue, the method for the estimation of the plasma or tissue volume, and other factors. Even with a more general approach such as model-independent analysis, first-order drug elimination is often assumed in the calculation of In selecting a model for data analysis, the pharmacokineticist may choose more than one method of modeling, depending on many factors, including experimental condition, study design, and completeness of data. The goodness-of-fit to the model and the desired pharmacokinetic parameters are other considerations. Each estimated pharmacokinetic parameter has an inherent variability because of the variability of the biologic system and the observed data. Moreover, because pharmacokinetic studies are performed on a limited number of subjects, the estimated pharmacokinetic parameters may not be representative of the entire population.
In spite of difficulties in the construction of these pharmacokinetic models, such models have been extremely useful in describing the time course of drug action, improving drug therapy by enhancing drug efficacy, and minimizing adverse reactions through more accurate dose regimens. Pharmacokinetic models are also applied to the development of new drug delivery systems. Three main types of pharmacokinetic models—physiologic, compartment, and statistical moment approach models—are discussed in this chapter.
The human body is composed of organ systems containing living cells bathed in an extracellular aqueous fluid (see Chapter 10). Both drugs and endogenous substances, such as hormones, nutrients, and oxygen, are transported to the organs by the same network of blood vessels (arteries). The drug concentration within a target organ depends on plasma drug concentration, the rate of blood flow to an organ, and the rate of drug uptake into the tissue. Physiologically, uptake (accumulation) of drug by organ tissues occurs from the extracellular fluid, which equilibrates rapidly with the capillary blood in the organ. Some drugs cross the plasma membrane into the interior fluid (intracellular water) of the cell (Fig. 22-1).
In describing drug transfer, the physiologic pharmacokinetic model divides a body organ into three parts: capillary vessels, extracellular space, and intracellular space.
In addition to drug accumulation, some organs of the body are involved in drug elimination, either by excretion (eg, kidney) or by metabolism (eg, liver). The elimination of drug by an organ may be described by drug clearance in the organ (see Chapters 6 and 11). The liver is an example of ...